Foot-and-mouth disease virus replication in bovine epithelia and the relationship to cellular type/differentiation and cytopathology

Foot-and-mouth disease virus (FMDV) causes a highly contagious disease that can affect cattle, sheep and pigs, and in some individuals (ruminants only) it can cause persistent infections resulting in carrier animals. A carrier is defined as an animal from which live virus can be recovered for longer than 28 days after exposure. There is considerable field evidence to indicate that these carrier animals may precipitate new outbreaks of disease and their occurrence significantly constrains trade in live susceptible animals and their products. FMD remains the single most important constraint to international trade in live animals and animal products. Outbreaks prevent developing countries from gaining access to lucrative export markets and within the developed world where the disease has been eradicated the reappearance of the disease can still cause devastating economic consequences as was vividly demonstrated in the UK in 2001. Despite its profound impact on animal health, the factors that regulate pathogenesis and persistence are still poorly understood. During the acute phase of FMD, FMDV rapidly infects cells and produces lesions on the tongue and foot covered skin that has a layer of dead cells. We have shown that samples collected from these sites contain the highest levels of virus. In contrast, there are no lesions in the throat and soft palate covered by skin that has no layer of dead cells even when they have high levels of virus. In addition, we have shown that FMDV were predominantly present in the deeper layers of skin tissue of both tongue and foot during disease and in the soft palate during persistence. The reasons for why the virus cannot produce lesions in the soft palate skin despite their presence in the deep skin layer are not understood. It is possible that infection of the soft palate skin involves a slower rate of viral growth that does not lead to the production of observable lesions. This could be because the cells are at a different stage of division or differentiation or that the cells in these tissues are different. Even though these are attractive possibilities the necessary studies aimed at answering these questions using animals infected with FMDV have not been carried out. Therefore, this proposal seeks to understand precisely the association between cell type, cell status, virus growth and outcome of infection. This may reveal why lesions do not occur at the soft palate and provide an explanation as to why the virus remains in this type of skin for longer without causing damage while it can be cleared from other skin even though it has been damaged.

Foot-and-mouth disease virus (FMDV) causes a highly contagious disease that can affect cattle, sheep and pigs, and in some ruminants it can cause persistent infections resulting in carrier animals. Foot-and-mouth (FMD) remains the single most important constraint to trade in live animals and animal products. During the acute phase, FMDV kills epithelial cells rapidly in the stratified, cornified squamous epithelia, resulting in vesicular lesions on feet and mouth. In contrast, there are no evident lesions or signs of cytopathic effect on pharyngeal region (dorsal soft palate and nasopharynx) covered by stratified, non-cornified squamous epithelia even when this region contains relatively high levels of viral RNA. In addition, FMDV RNA was predominantly localised in the basal cells of both mouth and foot epithelium during disease with later persistence also in the basal cell layer in the epithelia of dorsal soft palate. The mechanism that underlies these observations has not been identified yet. In vitro model of FMDV persistent infection implies that cell variation could affect whether cells are killed or survive. Non-cornified and cornifed stratified squamous epithelia have different histological features and a distinct expression of differentiation markers. It is possible that the whether or not FMDV lytically replicates in vivo is dependent on cell-type and infection of non-cornified epithelial cells involves a slower rate of viral replication that causes no cytopathology. The restriction of FMDV to the basal cell layer of epithelia suggests a possible link between FMDV replication in vivo and the cell status. This proposal seeks to define precisely the association between cell type, cell status, virus replication and outcome of infection. This may reveal why lesions/cytopathology do not occur at pharyngeal sites and provide an explanation for the establishment and maintenance of FMDV persistence.